The Ordovician–Silurian (O–S) transition was a critical interval in geological history. Multiple geochemical methods are used to explore the changes in oceanic environment. The Nd isotopic compositions in the Yangtze Sea are controlled by two sources: the continental erosion and the Panthalassa Ocean. HighεNd(t) values during the Katian, late Hirnantian and Rhuddanian intervals are associated with the high sea level, which resulted in less terrestrial input based on the low Ti/Al and Zr/Al ratios. In contrast, lowεNd(t) values during the early Hirnantian interval are related to the sea-level fall; in this case, the exposure of submarine highs and the growth of Yangtze Oldlands could lead to more continental materials being transported into the Yangtze Sea based on high Ti/Al and Zr/Al ratios. In addition, the negativeεNd(t) excursion can also be attributed to the weak circulation between the Yangtze Sea and Panthalassa Ocean when sea level was low. Furthermore, the sea-level eustacy plays a significant role in the changes in redox water conditions. The redox indices, mainly U_EF, Ce/Ce* and C_org/P_T, across the O–S transition show a predominance of anoxic ocean over the Yangtze Sea during the Katian, late Hirnantian and Rhuddanian intervals, and an oxygenated episode was briefly introduced during the early Hirnantian period because of the fall in sea level. The Late Ordovician biotic crisis was marked by two-phase extinction events, and the change in sea level and redox chemistry may be the important kill mechanisms.